Upper abdominal dyspepsia is symptomatic of a variety of diseases such as ulcers, biliary conditions, pancreatitis and gastrooesophageal reflux. However, the symptoms (heartburn, regurgitation and epigastric pain) often associated with such conditions may also occur without apparently being attributable to any specific clinical conditions observed by X-ray or endoscopic analyses.
Thus, the symptoms are very common, at least once in a while, even among otherwise healthy individuals. It is estimated that about 50-60% of the adult population in the United States suffer from one form or another of acute upper gastrointestinal distress. The short-term or prolonged use of antacids is therefore widespread.
The antacid effect of most of the antacid compositions currently in use resides in their ability to neutralize gastric acids, resulting in an increased pH of the gastric contents. The acid neutralizing effect of such conventional antacids is known to be brief in vivo, which is ascribable to two principal causes: the normal gastric emptying rate which causes the composition to be transferred to the intestines before its acid neutralizing and buffering capacities have been exhausted, and "acid rebound" or increased acid secretion induced by increased release of gastrin from the so-called G cells of the antrum which are pH sensitive, the increased production of gastrin occurring at a pH of the gastric contents of about 4-5 or more. For these reasons, the acidity of the gastric contents will usually have reached its normal level 1-2 hours after ingestion of the antacid so that a dosage regimen involving the ingestion of repeated antacid dosages may be required, in particular for the long-term treatment of gastric conditions such as ulcers, rather than for short-term relief of dyspepsia.
The currently employed antacids usually contain one or more alkali metal or alkaline earth metal salts, aluminum salts or, less usually, bismuth salts as acid neutralizing agents. The most commonly employed mineral salts are sodium bicarbonate, calcium carbonate, aluminum salts or magnesium salts.
Sodium bicarbonate is known as a potent, effective and rapid-acting antacid which, however, only exhibits a short-term effect. It is a systemic antacid which is not recommended for prolonged use or in large doses as systemic absorption of the sodium ion in large quantities may cause alkalosis which is characterized by elevated levels of carbon dioxide and an increased pH in the plasma. Symptoms of alkalosis include headache, mental confusion and anorexia.
Calcium carbonate which is a non-systemic gastric antacid is known to cause rapid, prolonged and effective neutralization of gastric acid, but is not recommended as an antacid, primarily because of its "acid rebound" effect. Studies have shown that oral administration of an isotonic calcium chloride solution results in increased gastric acid secretion both in healthy individuals and, particularly, in ulcer patients (50-75%). In another study, free calcium in the stomach has been found to release gastrin which in turn, as described above, induces the formation of gastric acid. Apart from acid rebound, it may cause hypercalcaemia and constipation.
The most commonly employed aluminum salts are the hydroxide, carbonate or phosphate, primarily the hydroxide. Its acid neutralizing capacity is lower than that of other conventional antacids, and it may cause constipation. Aluminum salts are therefore often combined with magnesium salts, such as the oxide, hydroxide, carbonate and trisilicate, which have a higher acid neutralizing capacity than the aluminum salts, but which may also cause diarrhoea. In combination preparations, the two components are balanced to offset the effect of either on gastrointestinal functions. A combination of aluminum and magnesium hydroxide gels is present in many commercial antacids. Recently, aluminum has become suspected of contributing to the development of presenile dementia (Alzheimer's disease) for which reason its use as an antacid should perhaps be discouraged.
Thus, the use of the various alkaline salts discussed above is associated with several drawbacks in the form of a number of adverse effects of major or minor severity. These adverse effects are of greater importance in case of long-term treatment involving a high antacid dosage. In recent years other approaches to gastrointestinal diseases have been attempted, which have primarily been concerned with reducing acid secretion. Agents responsible for a reduction of acid secretion in the stomach comprise anticholinergics and H.sub.2 -receptor antagonists. Such agents, however, suffer from the serious disadvantage of having serious adverse effects in larger doses as well as being available on prescription only (which is a drawback since antacids are often used for short-term relief of dyspeptic symptoms so that reliable and safe antacid preparations should preferably be available as over-the-counter products).
It is generally recognized that the efficacy of an antacid should be evaluated according to the following parameters: the level of acid neutralizing capacity, the period of latency before the acid neutralizing effect sets in, i.e. before the pH is increased to 3, the highest pH measured and the duration of the period during which the pH is in the range of 3-5 (it is desirable that this period should be as long as possible). Although most of the antacids mentioned above show a high score when tested according to these parameters in vitro, their in vivo performance is less convincing due to the acid rebound and gastric emptying effects described above.
Therefore, there is a need for a safe, reliable antacid composition which exhibits the above-mentioned desirable properties of a high acid neutralizing capacity and prolonged effect without being subject to the acid rebound effect common to several of the known antacids, and which has few, if any, adverse effects.